Human cytomegalovirus (HCMV) is a ubiquitous herpes virus causing mild or subclinical disease in immunocompetent adults. However, severe complications may be encountered in immunocompromised individuals. HCMV is a systemic infection that may infect several sites in the body, including the retina, gastrointestinal tract, lungs, liver and central nervous system. Initially it is was shown that human cytomegalovirus (HCMV) required eleven distinct loci for origin-dependent DNA replication. In later studies it was demonstrated that, of the eleven loci originally described, UL84 appeared to be the only non- core replication protein required for oriLyt-dependent replication. This fact, coupled with the observation that RNA-DNA hybrid structures are present within HCMV oriLyt, suggests the possibility that HCMV may have a mode of initiation of DNA replication unlike that of other herpesviruses. UL84 may be the key factor involved in initiation of HCMV DNA replication and, therefore, an ideal target for chemotherapeutic agents needed to control infection. To this end, this proposal will define the role of UL84 in the initiation of HCMV DNA replication and effects on cellular processes. The UL84 protein is required for HCMV DNA replication as demonstrated in transient assays and with a viral mutant. The elucidation of a function for UL84 will allow for the development of anti-HCMV drugs. Our hypothesis is that UL84 is involved in the initiation of HCMV DNA replication by a direct interaction with the origin of replication, oriLyt, and participates in the regulation of host cell RNA processing.